Psychotropic agents and uses thereof

ABSTRACT

Novel amisulpride derivatives and pharmaceutical compositions thereof are disclosed. The amisulpride derivative disclosed herein or a pharmaceutical composition thereof may have better membrane permeability compared to amisulpride. The amisulpride derivative disclosed herein or a pharmaceutical composition thereof may be used for antagonizing dopamine and/or serotonin (e.g., 5-HT2a) and/or a2 receptor in a subject, either individually or in combination with other CNS active agents. The amisulpride derivative disclosed herein or a pharmaceutical composition thereof may be used for treating one or more conditions responsive to modulation of dopamine and/or serotonin (e.g., 5-HT2a) and/or α2 receptor in a subject, either individually or in combination with other CNS active agents. The amisulpride derivative disclosed herein or a pharmaceutical composition thereof may be used for treating one or more disorders associated with an abnormality in levels of dopamine and/or serotonin in the brain, either individually or in combination with other CNS active agents.

PRIORITY CLAIM

This application is a continuation application of U.S. application Ser.No. 15/824,966, filed Nov. 28, 2017, which claims the benefit of U.S.Provisional Application No. 62/427,062, filed Nov. 28, 2016, and U.S.Provisional Application No. 62/508,263, filed May 18, 2017, both ofwhich are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention is generally in the field of pharmaceuticalcompositions and methods for the treatment of neuropsychiatric and/orpsychological diseases or disorders.

BACKGROUND

Schizophrenia is a chronic debilitating mental illness affecting aboutone percent of the population. The disease manifests in delusionalbehavior, dysfunctional thinking, agitated body movement, socialwithdrawal, and depression. Schizophrenia patients suffer a profoundlyreduced quality of life, and are ten times more likely to commit suicidethat the general population.

Dopamine (particularly D₂ and D₃) antagonists are well recognized asimproving symptoms of schizophrenia, and have been used clinically assuch for decades. In the past twenty years it has become recognized thattreatment of schizophrenia, as with many mental illnesses, benefits fromengaging multiple receptors including serotonergic and adrenergic.Despite, literally, dozens of approved drugs to treat schizophrenia thedisease remains poorly treated in many patients. Side effects of currentmedications include: dyskinesia, akathisia, weight gain, mooddisturbances, sexual dysfunction, sedation, orthostatic hypotension,hypersalivation, and (in some cases) arganulocytosis.

Amisulpride(4-amino-N-(((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide)is an antipsychotic patented in 1981. Amisulpride binds selectively tothe human dopaminergic D₂ (K_(i) 2.8 nM) and D₃ (K_(i) 3.2 nM) receptorsubtypes without any affinity for D₁, D₄ and D₅ receptor subtypes.Unlike classical and atypical neuroleptics, amisulpride displays lowaffinity for serotonin, alpha-adrenergic, histamine receptor subtypes,muscarinic receptors and sigma sites though it has also beendemonstrated to bind 5-HT_(2B) and HT_(7a) receptors with low doubledigit nM K_(i). This ability of amisulpride to bind 5-HT receptors isthought to result in amisulpride's ability to treat symptoms ofdepression (sometimes noted in schizophrenia patients). Interestingly,compared to other antipsychotics, amisulpride is not noted to have anyactivity at the 5-HT_(2a) receptor.

Despite the unique activities of amisulpride, amisulpride has lowability to cross blood brain barrier (BBB) to interact with thereceptors in the brain. In a 2014 study, passive diffusion ofamisulpride across a PAMPA membrane (Pe) was the lowest of 30psychiatric drugs tested. Thus, dosing of amisulpride is high, typically400 to 800 mg/d (though up to 1,200 mg/day is not uncommon). Such a highdose may cause adverse effects to the treated subjects.

SUMMARY OF THE INVENTION

Provided herein are novel amisulpride derivatives and pharmaceuticalcompositions thereof. In certain embodiments, the amisulpridederivatives disclosed herein are dopamine and/or serotonin antagonists.In certain embodiments, the amisulpride derivatives disclosed hereinhave improved membrane (e.g., BBB) permeability compared to amisulpride.In certain embodiments, the amisulpride derivatives can act as centralnervous system (CNS) dopamine and/or serotonin antagonists. Theseamisulpride derivatives have structures of Formula I, Formula IA,Formula IB or Formula IC disclosed herein, including pharmaceuticallyacceptable salts thereof, and stereoisomers thereof (e.g., Formula I-S,Formula I-R, Formula IA-S, Formula IA-R, Formula IB-S, Formula IB-R,Formula IC-S, and Formula IC-R). Provided herein are also deuteratedanalogs of the amisulpride derivatives disclosed herein.

Also provided herein are methods for delivering a dopamine and/orserotonin (e.g., 5-HT2a) and/or alpha-2 adrenergic (a2) receptorantagonist to the brain of a subject comprising administering to thesubject an amisulpride derivative disclosed herein or a pharmaceuticalcomposition thereof; and the dopamine and/or serotonin and/or a2receptor antagonist level in the brain is higher than administering tothe subject amisulpride at a comparable dose.

Also provided herein are methods for antagonizing dopamine and/orserotonin (e.g., 5-HT2a) and/or α2 receptor in a subject comprisingadministering to a subject the amisulpride derivatives disclosed hereinor pharmaceutical compositions thereof, either individually or incombination with other CNS active agents.

Also provided herein are methods for treating one or more conditionsresponsive to modulation of dopamine and/or serotonin (e.g., 5-HT2a)and/or α2 receptor in a subject comprising administering to a subjectthe amisulpride derivatives disclosed herein or pharmaceuticalcompositions thereof, either individually or in combination with otherCNS active agents.

Also provided herein are methods for treating one or more disordersassociated with an abnormality in levels of dopamine and/or serotonin inthe brain, comprising administering to a subject the amisulpridederivatives disclosed herein or pharmaceutical compositions thereof,either individually or in combination with other CNS active agents.

Examples of the conditions responsive to modulation of dopamine and/orserotonin (e.g., 5-HT2a) and/or α2 receptor and/or and the disordersassociated with abnormality in levels of dopamine and/or serotonin inthe brain include, e.g., without limitation, mental illnesses. Examplesof the mental illnesses include, without limitation, schizophrenia,symptoms of schizophrenia, schizoaffective disorder, bipolar disorder,depression, obsessive-compulsive disorder, Parkinson's psychosis,Alzheimer's psychosis, oppositional defiant disorder, aggression,suicidality, hostility, personality disorders, chronic fatigue syndrome,predominantly negative symptoms of schizophrenia, Charles BonnetSyndrome, autism, and Tourette's disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A: Novel object exploration data from a sub-chronic PCP NOR studyin rats (±SEM, n=10/group). Differences in Discrimination index ((timespent exploring novel−time spent exploring familiar)/total explorationtime) are depicted.

FIG. 1B: Discrimination index data from a sub-chronic PCR NOR study inrates (n=10/group). Differences in discrimination index ((time spentexploring novel−time spent exploring familiar)/total exploration time)are depicted.

FIG. 2: Total Ambulatory Distance (over 1 hour)±SEM (n=10/group). p<0.05for all treated groups compared to amphetamine.

DETAILED DESCRIPTION OF THE INVENTION

As disclosed herein, 4-amino substituted derivatives of amisulpride(also referred to as 4-amino amisulpride derivatives and 4-aminosubstituted amisulpride derivatives) showed improved membrane (e.g.,BBB) permeability and may be used to target relevant receptors in thebrain at a lower dose with less side effects to the treated subjectscompared to amisulpride. For example, a 4-amino substituted amisulpridederivative Compound 102 (also referred to as LB-102, N-methylamisulpride, and 4-methylamino substituted amisulpride derivative) wasprepared (Examples 1 and 2) and showed unexpectedly high membranepermeability improvement compared to that of amisulpride (Example 4,216.7 time improvement at pH 7.4, and 87.5 time improvement at pH 5).Stereoisomers of Compound 102 (Compound 103 and Compound 104) were alsoprepared (Example 3), as were other 4-amino amisulpride derivativesCompounds 105 to 110. Furthermore, the 4-amino substituted amisulpridederivatives showed effective binding to dopamine D₂ receptors andvarious CNS receptors (Examples 5-7). Unexpectedly, the 4-aminosubstituted amisulpride derivatives showed α2 (e.g., α2A, α2B, and α2C)receptor antagonism (Table 4, Example 7), while amisulpride displayedlow affinity for α2 receptor. The 4-amino substituted amisulpridederivative showed 2-HT_(2a) receptor antagonism (Table 4, Example 7),while amisulpride is not noted to have any activity at the 5-HT_(2a)receptor. Furthermore, Compound 102 and Compound 103 were shown torestore known object exploration behavior in rats with impaired abilityto discern between novel and familiar object in a Novel ObjectRecognition (NOR) assay (Example 8). The normalized amphetaminehyperactivities of Compounds 102 and 103 were statistically superior toor indistinguishable from that of amisulpride in an amphetamine-inducedLocomotor Activity (LMA) assay (Example 9).

4-Amino Substituted Amisulpride Derivatives

Provided herein are amisulpride derivatives having a structure ofFormula I:

including pharmaceutically acceptable salts and stereoisomers thereof,wherein:

R₁ is

andX and Z are the same or different and independently selected from thegroup consisting of hydrogen, alkyl (either branched or unbranched, suchas methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl), alkenyl(either branched or unbranched, such as methyl, ethyl, n-propyl,i-propyl, n-butyl, and s-butyl), alkynyl (either branched or unbranched,such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and s-butyl),cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl),cycloalkylalkyl (e.g., cyclopropylmethyl, cyclobutylethyl, andcyclopentylethyl), heterocyclyl, heterocyclylalkyl, aryl (e.g., phenyl,naphthyl, tetrahydronapthyl, indanyl, and biphenyl), arylalkyl (e.g.,—CH₂C₆H₅, and —C₂H₅C₆H₅), heteroarylalkyl (e.g., —CH₂C₆H₄N, and—C₂H₅C₆H₄N), and heteroaryl with one or two or three or more hetero ringatoms (such as pyridine, pyrrole, furan, thiophene, or pyrimidine),optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroarylalkyl, andheteroaryl groups are further substituted with one or more substitutiongroups selected from the group consisting of halogens such as chlorine,bromine and fluorine, amines, hydroxy groups, carboxylic acids, nitrogroups, carbonyl and other alkyl and aryl groups as defined herein; withthe proviso that at least one of X and Z is not hydrogen.

In certain embodiments, the amisulpride derivative is a stereoisomerhaving a structure of Formula I-S:

-   -   including pharmaceutically acceptable salts thereof, wherein Z,        X, and R₁ are defined the same as above with respect to Formula        I.

In certain embodiments, the amisulpride derivative is a stereoisomerhaving a structure of Formula I-R:

-   -   including pharmaceutically acceptable salts thereof, wherein Z,        X, and R₁ are defined the same as above with respect to Formula        I.

In certain embodiments, the amisulpride derivative is a 4-aminosubstituted derivative of amisulpride having a structure of Formula IA:

-   -   including pharmaceutically acceptable salts and stereoisomers        thereof, and X and Z are defined the same as above with respect        to Formula I.

In certain embodiments, the 4-amino substituted derivative ofamisulpride is a stereoisomer having a structure of Formula IA-S:

-   -   including pharmaceutically acceptable salts thereof, and X and Z        are defined the same as above with respect to Formula I.

In certain embodiments, the 4-amino substituted derivative ofamisulpride is a stereoisomer having a structure of Formula IA-R:

-   -   including pharmaceutically acceptable salts thereof, and X and Z        are defined the same as above with respect to Formula I.

In certain embodiments, the amisulpride derivative is a 4-aminosubstituted derivative of amisulpride having a structure of Formula IB:

-   -   including pharmaceutically acceptable salts and stereoisomers        thereof, and Z is defined the same as above with respect to        Formula I with the proviso that Z is not H.

In certain embodiments, the 4-amino substituted derivative ofamisulpride is a stereoisomer having a structure of Formula IB-S:

-   -   including pharmaceutically acceptable salts thereof, and Z is        defined the same as above with respect to Formula I with the        proviso that Z is not H.

In certain embodiments, the 4-amino substituted derivative ofamisulpride is a stereoisomer having a structure of Formula IB-R:

-   -   including pharmaceutically acceptable salts thereof, and Z is        defined the same as above with respect to Formula I with the        proviso that Z is not H.

In certain embodiments, the amisulpride derivative has a structure ofFormula IC:

-   -   including pharmaceutically acceptable salts and stereoisomers        thereof, and Z is defined the same as above with respect to        Formula I with the proviso that Z is not H.

In certain embodiments, the amisulpride derivative is a stereoisomerhaving a structure of Formula IC-S:

-   -   including pharmaceutically acceptable salts thereof, and Z is        defined the same as above with respect to Formula I with the        proviso that Z is not H.

In certain embodiments, the amisulpride derivative is a stereoisomerhaving a structure of Formula IC-R:

-   -   including pharmaceutically acceptable salts thereof, and Z is        defined the same as above with respect to Formula I with the        proviso that Z is not H.

In certain embodiments, the amisulpride derivatives disclosed hereinhave greater membrane (e.g., BBB) permeability than amisulpride. Incertain embodiments, the amisulpride derivatives disclosed herein aredopamine and/or serotonin and/or α2 antagonists. For example, theamisulpride derivatives disclosed herein bind to dopamine D₂ and/or D₃receptors. In certain embodiments, the amisulpride derivatives disclosedherein more selectively bind to dopamine D₂ and/or D₃ receptor overdopamine D₁, D₄ and/or D₅ receptor. In certain embodiments, theamisulpride derivatives disclosed herein are capable of interactingdopamine and/or serotonin and/or α2 receptors in CNS.

Provided herein are also deuterated analogs of the amisulpridederivatives disclosed herein, wherein one or more hydrogens of theamisulpride derivatives are replaced by deuterium. In certainembodiments, the one or more deuteriums in the deuterated analog arepresent in at least 100 times the natural abundance level.

Provided herein are pharmaceutical compositions comprising one or moreof the amisulpride derivatives and deuterated analogs thereof disclosedherein and a pharmaceutically acceptable carrier. In certainembodiments, the one or more of the amisulpride derivatives thepharmaceutical compositions comprise are substantially enantiomericallypure, and such pharmaceutical compositions are also referred to assubstantially enantiomerically pure pharmaceutical compositions. Incertain embodiments, the term “substantially enantiomerically pure”means enantiomerical purity of about 50% or higher, about 60% or higher,about 70% or higher, about 80% or higher, about 90% or higher, about 95%or higher, or about 98% or higher.

Also provided herein are methods for delivering a dopamine and/orserotonin (e.g., 5-HT_(2a)) and/or α2 receptor antagonist to the brainof a subject comprising administering to the subject one or more ofamisulpride derivatives and deuterated analogs thereof disclosed herein,or a pharmaceutical composition thereof; and the dopamine and/orserotonin (e.g., 5-HT_(2a)) and/or α2 receptor antagonist level in thebrain is higher than administering to the subject amisulpride at acomparable dose. In certain embodiments, the amisulpride derivatives,deuterated analogs, and/or the pharmaceutical composition aresubstantially enantiomerically pure.

Also provided herein are methods for antagonizing dopamine and/orserotonin (e.g., 5-HT_(2a)) and/or α2 receptor in a subject comprisingadministering to a subject one or more of amisulpride derivatives anddeuterated analogs thereof disclosed herein or a pharmaceuticalcomposition thereof, either individually or in combination with otherCNS active agents. In certain embodiments, the amisulpride derivatives,deuterated analogs, and/or the pharmaceutical composition aresubstantially enantiomerically pure.

Also provided herein are methods for treating one or more conditionsresponsive to modulation of dopamine and/or serotonin (e.g., 5-HT_(2a))and/or α2 receptor in a subject comprising administering to a subject atherapeutically effective amount of one or more of amisulpridederivatives and deuterated analogs thereof disclosed herein or apharmaceutical composition thereof, either individually or incombination with other CNS active agents. In certain embodiments, theamisulpride derivatives, deuterated analogs, and/or the pharmaceuticalcomposition are substantially enantiomerically pure.

Provided herein are methods for treating one or more disordersassociated with an abnormality in levels of dopamine and/or serotonin inthe brain in a subject comprising administering to the subject atherapeutically effective amount of one or more of amisulpridederivatives and deuterated analogs thereof disclosed herein, or apharmaceutical composition thereof. In certain embodiments, theamisulpride derivatives, deuterated analogs and/or the pharmaceuticalcomposition are substantially enantiomerically pure.

In certain embodiments, the therapeutically effective amount of theamisulpride derivatives disclosed herein or the pharmaceuticalcomposition thereof is lower than the that of amisulpride. Accordingly,the methods disclosed herein may result in fewer adverse events to thesubject treated.

Examples of conditions responsive to modulation of dopamine and/orserotonin (e.g., 5-HT_(2a)) and/or α2 receptor and/or disordersassociated with an abnormality in levels of dopamine and/or serotonin inthe brain include, e.g., without limitation, mental illnesses. Examplesof the mental illnesses include, without limitation, schizophrenia,symptoms of schizophrenia, schizoaffective disorder bipolar disorder,depression, obsessive-compulsive disorder, Parkinson's psychosis,Alzheimer's psychosis, oppositional defiant disorder, aggression,suicidality, hostility, personality disorders, autism, chronic fatiguesyndrome, predominantly negative symptoms of schizophrenia, CharlesBonnet Syndrome, and Tourette's disorder.

As used herein, the singular for “a,” “an,” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a cell” includes a plurality of cells, including mixturesthereof. Similarly, use of “a compound” for treatment of preparation ofmedicaments as described herein contemplates using one or more compoundsof the invention for such treatment or preparation unless the contextclearly dictates otherwise.

As used herein, the term “comprising” is intended to mean that thecompositions and methods include the recited elements, but not excludingothers. Thus, a composition consisting essentially of the elements asdefined herein would not exclude trace contaminants from the isolationand purification method and pharmaceutically acceptable carriers, suchas phosphate buffered saline, preservatives, and the like. “Consistingof” shall mean excluding more than trace elements of other ingredientsand substantial method steps for administering the composition of thisinvention. Embodiments defined by each of the transitional terms arewithin the scope of this invention.

The term “alkyl” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation. Unless otherwise specified, the term “alkyl” refers to agroup having one, two, three, four, five, six, seven, or eight carbonatoms (for example, one to six carbon atoms, or one to four carbonatoms), and which is attached to the rest of the molecule by a singlebond. Examples of alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, t-butyl, s-butyl, n-pentyl, ands-pentyl.

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched orbranched chain. Unless otherwise specified, the term “alkenyl” refers toa group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, e.g.,ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

The term “alkynyl” refers to a straight or branched chain hydrocarbylradical having at least one carbon-carbon triple bond. Unless otherwisespecified, the term “alkynyl” refers to a group having in the range of2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (for instance, 2 to10, 2 to 10 carbon atoms), e.g., ethynyl, propynyl, and butnyl.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “cycloalkylalkyl” refers to a cycloalkyl group as defined abovedirectly bonded to an alkyl group as defined above.

The term “aryl” refers to a mono- or multi-cyclic aromatic radicalhaving in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl,tetrahydronapthyl, indanyl, and biphenyl.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above, e.g., —CH₂C₆H₅, and—C₂H₅C₆H₅.

The term “heterocyclyl” refers to a non-aromatic 3 to 15 member ringradical which, consists of carbon atoms and at least one heteroatomselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. The heterocyclic ring radical may be a mono-, bi-, tri- ortetracyclic ring system, which may include fused, bridged or spiro ringsystems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms inthe heterocyclic ring radical may be optionally oxidized to variousoxidation states. In addition, the nitrogen atom may be optionallyquaternized.

The term “heterocyclylalkyl” refers to a heterocyclyl group as definedabove directly bonded to an alkyl group as defined above.

The term “heteroaryl” refers to an optionally substituted 5-14 memberaromatic ring having one or more hetero ring atoms selected from thegroup consisting of N, O, and S as ring atoms. The heteroaryl may be amono-, bi- or tricyclic ring system. Examples of such heteroaryl ringradicals includes, but are not limited to, oxazolyl, thiazolylimidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl,benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl,quinolyl and isoquinolyl.

The term “heteroarylalkyl” refers to an heteroaryl group as definedabove directly bonded to an alkyl group as defined above, e.g.,—CH₂C₆H₄N, and —C₂H₅C₆H₄N.

The term “subject” refers to a mammal, such as a domestic pet (forexample, a dog or cat), or human. In certain embodiments, the subject isa human.

The phrase “effective amount” refers to the amount which, whenadministered to a subject or patient for treating a disease, issufficient to effect such treatment for the disease.

“Treatment” or “treating” includes (1) inhibiting a disease in a subjector patient experiencing or displaying the pathology or symptomatology ofthe disease (e.g., arresting further development of the pathology and/orsymptomatology), (2) ameliorating a disease in a subject or patient thatis experiencing or displaying the pathology or symptomatology of thedisease (e.g., reversing the pathology and/or symptomatology), and/or(3) effecting any measurable decrease in a disease in a subject orpatient that is experiencing or displaying the pathology orsymptomatology of the disease.

The term “pharmaceutically acceptable carrier” refers to a carrier thatdoes not cause an allergic reaction or other untoward effect in patientsto whom it is administered and are compatible with the other ingredientsin the formulation. Pharmaceutically acceptable carriers include, forexample, pharmaceutical diluents, excipients or carriers suitablyselected with respect to the intended form of administration, andconsistent with conventional pharmaceutical practices. For example,solid carriers/diluents include, but are not limited to, a gum, a starch(e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.,microcrystalline cellulose), an acrylate (e.g., polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.Pharmaceutically acceptable carriers may further comprise minor amountsof auxiliary substances such as wetting or emulsifying agents,preservatives or buffers, which enhance the shelf life or effectivenessof the therapeutic agent.

The term “salt” used herein is not limited as long as the salt is formedwith a compound of the amisulpride derivatives and is pharmaceuticallyacceptable; preferred examples of salts include a hydrohalide salt (forinstance, hydrochloride, hydrobromide, hydroiodide and the like), aninorganic acid salt (for instance, sulfate, nitrate, perchlorate,phosphate, carbonate, bicarbonate and the like), an organic carboxylatesalt (for instance, acetate salt, maleate salt, tartrate salt, fumaratesalt, citrate salt and the like), an organic sulfonate salt (forinstance, methanesulfonate salt, ethanesulfonate salt, benzenesulfonatesalt, toluenesulfonate salt, camphorsulfonate salt and the like), anamino acid salt (for instance, aspartate salt, glutamate salt and thelike), a quaternary ammonium salt, and the like. In addition,hydrochloride salt, sulfate salt, methanesulfonate salt, acetate saltand the like are preferred as “pharmacologically acceptable salt” of theamisulpride derivatives disclosed herein.

Isomers of the amisulpride derivatives disclosed herein (e.g., geometricisomers, optical isomers, rotamers, tautomers, and the like) can bepurified using general separation means, including for examplerecrystallization, optical resolution such as diastereomeric saltmethod, enzyme fractionation method, various chromatographies (forinstance, thin layer chromatography, column chromatography, glasschromatography and the like) into a single isomer.

Pharmaceutical Formulations and Routes of Administration

The amisulpride derivatives disclosed herein and/or deuterated analogsthereof may be administered by a variety of routes including orally andby injection (e.g. subcutaneously, intravenously, andintraperitoneally). The amisulpride derivatives disclosed herein may beformulated into a pharmaceutical composition for use in the disclosedmethods. Such compositions are prepared in accordance with acceptablepharmaceutical procedures such as described in Remington'sPharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, MackPublishing Company, Eaton, Pa. (1985), which is incorporated herein byreference.

The amisulpride derivatives disclosed herein and/or deuterated analogsthereof may be administered orally in the form of a solid or liquiddosage form. In both, the amisulpride derivatives disclosed hereincompound may be coated in a material to protect it from the action ofacids and other natural conditions which may inactivate the compound.The amisulpride derivatives disclosed herein may be formulated asaqueous solutions, liquid dispersions, (ingestible) tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, and wafers.The oral dosage forms may include excipients known in the art, such asbinders, disintegrating agents, flavorants, antioxidants, andpreservatives. Liquid dosage forms may include diluents such as salineor an aqueous buffer.

The amisulpride derivatives disclosed herein and/or deuterated analogsthereof may also be administered by injection. Formulations suitable forinjection may include sterile aqueous solutions (where water soluble) ordispersions, and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersions. The pharmaceuticalcomposition may be sterile and be fluid to the extent that easysyringability exists. It may be stable under the conditions ofmanufacture and storage and be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. Thepharmaceutically acceptable carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (such as,glycerol, propylene glycol, and liquid polyethylene glycol), suitablemixtures thereof, and vegetable oils. The proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionand by the use of surfactants. Prevention of the action ofmicroorganisms can be achieved by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, and ascorbic acid.In many cases, it will be preferable to include isotonic agents, forexample, sugars, sodium chloride, or polyalcohols such as mannitol andsorbitol, in the composition. Prolonged absorption of the injectablecompositions can be brought about by including in the composition anagent which delays absorption, for example, aluminum monostearate orgelatin.

Sterile injectable solutions can be prepared by incorporating thetherapeutic compound in the required amount in an appropriate solventwith one or a combination of ingredients enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the therapeutic compound into a sterile carrier whichcontains a basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, the methods of preparationinclude vacuum drying and freeze-drying which yields a powder of theactive ingredient (i.e., the therapeutic compound) plus any additionaldesired ingredient from a previously sterile-filtered solution thereof.

The actual dosage amount of the compound administered to a subject maybe determined by physical and physiological factors such as age, sex,body weight, severity of condition, the type of disease being treated,previous or concurrent therapeutic interventions, idiopathy of thesubject and on the route of administration. These factors may bedetermined by a skilled artisan. The practitioner responsible foradministration will typically determine the concentration of activeingredient(s) in a composition and appropriate dose(s) for theindividual subject.

In one embodiment, a human subject is administered the daily doses offrom about 0.01 mg/kg to about 100 mg/kg.

Single or multiple doses of the compounds are contemplated. Desired timeintervals for delivery of multiple doses can be determined by one ofordinary skill in the art employing no more than routineexperimentation. As an example, subjects may be administered two dosesdaily at approximately 12 hour intervals. In some embodiments, thecompound is administered once a day.

The amisulpride derivatives disclosed herein or pharmaceuticalcompositions thereof may be administered on a routine schedule. As usedherein a routine schedule refers to a predetermined designated period oftime. The routine schedule may encompass periods of time which areidentical or which differ in length, as long as the schedule ispredetermined. For instance, the routine schedule may involveadministration twice a day, every day, every two days, every three days,every four days, every five days, every six days, a weekly basis, amonthly basis or any set number of days or weeks there-between.Alternatively, the predetermined routine schedule may involveadministration on a twice daily basis for the first week, followed by adaily basis for several months. In other embodiments, the inventionprovides that the amisulpride derivatives disclosed herein orpharmaceutical compositions thereof agent(s) may be taken orally andthat the timing of which is or is not dependent upon food intake. Thus,for example, the agent can be taken every morning and/or every evening,regardless of when the subject has eaten or will eat.

Combination Therapy

In addition to being used as a monotherapy, the amisulpride derivativesdisclosed herein or pharmaceutical compositions thereof may also finduse in combination therapies. Effective combination therapy may beachieved with a single pharmaceutical composition or pharmacologicalformulation that includes both agents, or with two distinctpharmaceutical compositions or pharmacological formulations,administered at the same time, wherein one composition includes acompound of this invention, and the other includes the second agent(s).Alternatively, the therapy may precede or follow the other agenttreatment by intervals ranging from minutes to months.

The additional agent or agents may be selected from any agent or agentsuseful for treating a psychological disorder, for example any agent oragent and/or α2s useful for treating an imbalance of dopamine,serotonin, histamine, or glutamate. In one embodiment, the additionalagent or agent is useful in improving psychological function, e.g., anantipsychotic, such as quetiapine, geodon, zyprexa, latuda, olanzapine,risperidone, iloperidone, ziprasidone, clozapine, haloperidol,chlorpromazine, citrlopram, escitalopram, paroxetine, fluoxetine,fluvoxamine, sertraline, desvenlafaxine, duloxetine, milnacipran,venlafaxine, vilazodone, and combinations thereof.

Synthesis of the Amisulpride Derivatives

The amisulpride derivatives disclosed herein of the present inventioncan be prepared from amisulpride(4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide),which is readily available. The synthesis of amisulpride is described,for example, in U.S. Pat. No. 4,401,822.

The following synthesis for preparing the compounds of formula IB can beadapted to prepare other compounds of the present invention, such ascompounds of Formulas I, IA and IC. The compound of formula IB can beprepared by (a) treating amisulpride with a mixture of a carboxylic acidand its corresponding anhydride to obtain the corresponding amide, (b)reduction of the amide to the amine with a suitable reducing agent, forexample, borane:dimethyl sulfide to form a compound of Formula IB:

wherein Z is defined the same as above, and Z=—C—R.

This reaction scheme is shown below:

Similarly, compounds of Formula IA can be prepared by furthersubstituting the NH in the corresponding compound of Formula IB with thecorresponding X group; and compounds of Formula IC can be prepared byacylation of the aniline nitrogen in the corresponding compound ofFormula IB followed by reduction.

Additionally, 4-methylamino substituted amisulpride derivatives may beprepared by reacting amisulpride with N,N-dimethylformamide dimethylacetal to provide the corresponding amide, which is then reduced by areducing agent (e.g., NaBH₄, DMS:BH₃, Red-Al, and LiAlH₄) to provide thecorresponding 4-methylamino substituted amisulpride derivatives.

Stereoisomers of the amisulpride derivatives disclosed herein can beprepared similarly by using the corresponding stereoisomer ofamisulpride as the starting material. For example, synthesis of((S)-4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamidecan be carried out as described in U.S. Pat. No. 6,169,094, which isincorporated herein by reference. The S isomers of the amisulpridederivatives can be prepared using the S isomer of amisulpride (Schemes 3and 4). The R isomers of the amisulpride derivatives can be similarlyprepared using the R isomer of amisulpride.

When neither Z or X of an amisulpride derivative of Formula I ishydrogen, the amisulpride derivative (di-substituted 4-amino amisulpridederivative) may be prepared by a two-step substitution of the 4-aminogroup. First, the 4-amino group is substituted with a first substitutiongroup of Z or X as shown above to provide a mono-substituted 4-aminoamisulpride derivative; and then the mono-substituted 4-aminoamisulpride derivative is further substituted with a second substitutionat the 4-amino to provide the desired di-substituted 4-amino amisulpridederivative. See, e.g., Examples 3C and 3D.

Having described the invention with reference to the embodiments andillustrative examples, those in the art may appreciate modifications tothe invention as described and illustrated that do not depart from thespirit and scope of the invention as disclosed in the specification. Theexamples are set forth to aid in understanding the invention but are notintended to, and should not be construed to limit its scope in any way.The examples do not include detailed descriptions of conventionalmethods. Such methods are well known to those of ordinary skill in theart and are described in numerous publications. Further, all referencescited above and in the examples below are hereby incorporated byreference in their entirety, as if fully set forth herein.

EXAMPLES Example 1: Synthesis of4-formylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 1)

To a solution of4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(2 g, 5.5 mmol) in 20 mL formic acid, acetic anhydride (0.68 g, 6.6mmol) was added portionwise at 5-10° C. The reaction mixture was stirredovernight at room temperature, and carefully poured into aq. K₂CO₃ at5-10° C. Solid NaCl was added and the mixture was extracted with CHCl₃.The combined organic extracts were dried over Na₂SO₄, and the solventevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with 5-10% MeOH in CHCl₃ to afford1.82 g (83%) of a yellowish gum. ¹H NMR (400 MHz, CDCl₃): δ 1.1 (t, 3H,CH₃), 1.3 (t, 3H, CH₃) 1.6 (br s, 2H), 1.7 (br s, 2H), 1.9 (br s, 1H),2.3 (br s, 2H), 2.7 (br s, 1H), 2.9 (br s, 1H), 3.2 (q, 2H), 3.3 (br s,1H), 3.4 (br s, 1H), 3.7 (m, 1H), 4.1 (s, 3H, OCH₃), 8.4 (br s, 1H, NH),8.5 (s, 1H, H_(ar)), 8.6 (s, 1H, H_(ar)), 8.7 (s, 1H, CHO), 10.1 (s, 1H,NH). Expected Mol. Wt. [C₁₈H₂₇N₃O₅S]: 397.2, Observed Mol. Wt. 398.1[M+H⁺].

Example 2: Synthesis of4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 102)

To a solution of4-formylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 1, 1.82 g, 4.6 mmol) in 80 mL THF, BH₃Me₂S (1.09 mL, 11.5mmol) was added portionwise at 5-10° C. The reaction mixture was stirredat 60° C. for 3 h, and carefully quenched with MeOH (40 mL). Thereaction mixture was acidified with 10% HCl (15 mL) and the mixture wasstirred at 60° C. overnight. The solvents were evaporated under reducedpressure, the aqueous residue was diluted with H₂O and basified with aqNaOH to pH 10. The mixture was extracted with CHCl₃, the combinedorganic extracts were dried over Na₂SO₄ and evaporated. The residue waspurified by column chromatography on silica gel eluting with 5-10% MeOHin CHCl₃, following by purification by RP-HPLC eluting with a gradientMeCN-H₂O+0.1% TFA. The fractions containing the target material werepartially evaporated under reduced pressure, basified with aq NaOH to pH10, and extracted with CH₂Cl₂. The combined extracts were dried withNa₂SO₄ and evaporated under reduced pressure to afford the product as awhite solid after standing which solidified upon storage (0.93 g, 53%).¹H NMR (400 MHz, CDCl₃): δ 1.1 (t, 3H, CH₃), 1.3 (t, 3H, CH₃), 1.6 (m,3H), 1.9 (m, 1H), 2.2 (m, 2H), 2.5 (m, 1H), 2.7 (m, 1H), 2.9 (app d, 3H,NHCH₃), 3.1 (q, 2H, CH₂), 3.2 (m, 1H), 3.3 (m, 1H), 3.6 (m, 1H), 4.0 (s,3H, OCH₃), 6.1 (s, 1H, H_(ar)), 6.8 (br s, 1H, H_(ar)), 8.1 (br s, NH),8.5 (s, 1H, NH). ¹³C NMR (75 MHz, CDCl₃): δ 8.2, 14.9, 21.2, 29.0, 29.9,40.5, 47.8, 49.5, 53.7, 56.9, 61.0, 92.1, 110.2, 111.9, 136.1, 150.0,162.2, 164.0. Expected Mol. Wt. [C₁₈H₂₉N₃O₄S]: 383.2, Observed Mol. Wt.384.5 [M+H⁺].

Example 3: Synthesis of Stereoisomers (Compounds 103 and 104) ofCompound 102, and 4-amino amisulpride derivatives (Compounds 105 to 110)A): Synthesis of((S)-4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 103)

((S)-4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(11.1 g) was suspended in N,N-dimethylformamide dimethyl acetal (33 mL)and stirred for 2 hours at 90° C. The reaction mixture was cooled toroom temperature and NaBH₄ (4 g) was added portionwise. The mixture wasstirred at room temperature for 1 h. Saturated NaCHO₃ (50 mL) was addedto quench the reaction, and the resulting suspension was extracted withdichloromethane (2×50 mL). The organic phase was washed with brine,dried, filtered, and the solvent removed under reduced pressure. Theresidue was purified by column chromatography, eluting withCH₂Cl₂/MeOH/NH₃, to afford the product as a white solid that was furtherpurified by recrystallization from acetone (5.3 g).

¹H NMR (400 MHz, DMSO-d₆): δ 1.1 (2t, 2X3H, CH₃), 1.5 (2, 1H) 1.6 (m,2H), 1.8 (m, 1H), 2.1 (m, 1H), 2.3 (m, 2H), 2.5 (t, 1H), 2.6 (m, 1H),2.7 (m, 1H), 2.9 (t, 3H), 3.1 (3, 2H), 3.2 (m, 2H), 3.3 (m, 3H), 3.5 (m,1H), 4.0 (s, 3H, OCH₃), 6.3 (s, 1H_(ar)), 6.6 (m, 1H_(ar)), 8.1 (m, 1H,NH), 8.3 (5, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆): δ 7.56, 14.51, 23.05,28.54, 30.39, 41.64, 47.90, 48.77, 53.62, 56.79, 62.36, 94.45, 109.94,111.63, 135.68, 151.48, 163.14, 163.82. Expected Mol. Wt.[C₁₈H₂₇N₃O_(4S)] 383.2, Observed Mol. Wt. 384.4 [M+H⁺].

B): Synthesis of((R)-4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 104)

((S)-4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(11.2 g) was suspended in N,N-dimethylformamide dimethyl acetal (33 mL)and stirred for 2 hours at 90° C. The temperature was reduced to 70° C.and NaBH₄ (4 g) was added in 1 g portions at intervals of 20 minutes.After completion of the addition, the reaction mixture was left to stira further hour at 90° C. The reaction mixture was cooled in an ice bathand the reaction quenched by addition of 150 mL of saturated NaHCO₃. Theresulting solution was extracted with CH₂Cl₂ (5×50 mL) and the combinedorganic extracts dried over Na₂SO₄. Purification was achieved by columnchromatograpy, eluting with 10% MeOH/CH₂C₁₂ to afford 7.9 g of a whitesolid.

¹H NMR (300 MHz, CDCl₃): δ 1.2 (t, 3H, CH₃), 1.3 (t, 3H, CH₃), 1.7 (m,1H) 1.8 (m, 2H), 1.9 (m, 1H), 2.3 (m, 2H), 2.7 (m, 1H), 2.9 (m, 1H), 2.9(d, 1H), 3.1 (q, 2H), 3.3 (m, 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH₃), 6.1(s, 1H_(ar)), 6.8 (m, 1H_(ar)), 8.1 (m, 1H, NH), 8.6 (s, 1H, NH).Expected Mol. Wt. [C₁₈H₂₇N₃O₄S] 383.2, Observed Mol. Wt. 384.2 [M+H⁺].

C): Synthesis of(4-dimethylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 105)

4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(500 mg) was stirred in 10 mL formic acid at 30° C. for 21 h as NaBH₄ (8equiv) was added in two portions and washed with aqueous NaOH to afford408 mg of compound 105.

¹H NMR (400 MHz, CDCl₃): δ 1.2 (t, 3H, CH₃s), 1.7 (m, 1H), 1.8 (m, 2H),1.9 (m, 1H), 2.2 (m, 2H), 2.7 (m, 1H), 3.2 (m, 1H), 3.3 (m, 1H), 3.4 (q,2H), 4.0 (s, 3H, OCH₃), 6.8 (s, 1H_(ar)), 8.0 (s, 1H, NH) 8.8 (s, 1H).¹³C NMR (100 MHz, CDCl₃): δ 7.38, 14.21, 22.96, 28.40, 41.24, 46.14,48.39, 53.66, 56.11, 62.19, 104.94, 118.52, 126.17, 136.07, 157.93,161.56, 163.79. Expected Mol. Wt. [C₁₉H₃₁N₃O₄S] 397.2, Observed Mol. Wt.398.2 [M+H⁺].

D): Synthesis of(4-ethylmethylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 106)

4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(500 mg) was stirred in 6 mL 1,2-dichlororethane and sodiumtriacetoxyborohydride (1 g) and acetaldehyde (219 uL) were added andstirred at room temperature for 17 hours. The reaction was quenched byaddition of aqueous NaOH and the product extracted into dichloromethaneand purified by column chromatography to afford 98 mg of compound 106.

¹H NMR (400 MHz, CDCl₃): δ 1.2 (m, 6H, 2 CH₃s), 1.6 (m, 1H), 1.7 (m,2H), 1.9 (m, 1H), 2.2 (m, 2H), 2.6 (m, 1H), 2.9 (m, 1H), 3.1 (q, 1H),3.3 (m, 2H), 3.5 (q, 1H), 3.8 (m, 1H) 4.0 (s, 3H, OCH₃), 6.8 (s,1H_(ar)), 8.0 (s, 1H, NH) 8.8 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 7.36,12.84, 23.00, 28.42, 41.27, 42.99, 48.12, 52.30, 53.70, 56.16. 106.05,126.41, 130.05, 142.41, 157.554, 157.54, 161.48, 163.90. Expected Mol.Wt. [C₂₀H₃₃N₃O₄S] 411.3, Observed Mol. Wt. 412.3 [M+H⁺].

E): Synthesis of(4-ethylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 107)

(Ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500mg) was stirred in 6 mL 1,2-dichloroethane with 0.4 mL acetic acid. Themixture was cooled on an ice bath and 1.15 g sodiumtriacetoxyborohydride was added. The mixture was stirred at roomtemperature overnight. The reaction was quenched by addition of aqueousNaOH and the product extracted into dichloromethane and purified bycolumn chromatography and recrystallized from acetone/MTBE to afford 309mg of compound 107.

¹H NMR (400 MHz, CDCl₃): δ 1.1 (br t, 3H, CH₃), 1.3 (t, 3H, CH₃), 1.4(t, 3H, CH₃), 1.5-1.8 (m, 5H), 1.8 (m, 1H), 2.2 (m, 2H), 2.7 (m, 1H),2.9 (m, 1H), 3.1 (q, 2H), 3.3 (m 2H), 3.7 (m, 1H), 4.0 (s, 3H, OCH₃),6.1 (s, 1H_(ar)), 6.7 (s, 1H_(ar)), 8.1 (s, 1H, NH) 8.6 (s, 1H). ¹³C NMR(100 MHz, CDCl₃): δ 7.34, 14.17, 22.96, 28.47, 37.99, 41.35, 48.00,49.82, 53.70, 55.80, 62.38, 93.35, 110.89, 111.91, 136.76, 150.76,162.90, 164.29. Expected Mol. Wt. [C₁₉H₃₁N₃O₄S] 397.2, Observed Mol. Wt.398.2 [M+H⁺].

F): Synthesis of(4-isopropylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 108)

(Ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500mg) was stirred in 6 mL DMF with 0.12 mL acetone. The mixture was cooledon an ice bath and 0.3 mL TFA was added followed by addition of 441 mgsodium triacetoxyborohydride. The mixture was stirred at 40° C.overnight. The reaction mixture was poured into aqueous NaOH and theproduct extracted into dichloromethane and purified by columnchromatography to afford 550 mg of compound 108.

¹H NMR (400 MHz, CDCl₃): δ 1.1 (br t, 3H, CH₃), 1.2 (t, 3H, CH₃), 1.3(t, 6H, CH₃), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 1H), 2.2 (m, 1H), 2.6(m, 1H), 2.9 (m, 1H), 2.1 (q, 2H), 3.2 (m, 2H), 3.7 (m, 1H), 4.0 (s, 3H,OCH₃), 6.1 (s, 1H_(ar)), 6.7 (s, 1H_(ar)), 8.0 (s, 1H, NH) 8.6 (5, 1H).¹³C NMR (100 MHz, CDCl₃): δ 7.36, 22.45, 23.02, 28.48, 41.35, 44.15,49.95, 53.74, 55.80, 93.65, 111.83, 136.69, 150.03, 162.87, 164.33.Expected Mol. Wt. [C₂₀H₃₃N₃O₄S] 411.2, Observed Mol. Wt. 412.2 [M+H⁺].

G): Synthesis of(4-n-propylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 109)

(Ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500mg) was stirred in 6 mL 1,2-dichloroethane with 0.3 mL proprionaldehyde.Sodium triacetoxyborohydride (1.2 g) was added in two portions 10minutes apart, and the mixture was left to stir overnight. The reactionmixture was poured into aqueous NaOH and the product extracted intoethyl acetate and purified by column chromatography to afford 518 mg ofcompound 109.

¹H NMR (400 MHz, CDCl₃): δ 1.1 (br t, 3H, CH₃), 1.2 (t, 3H, CH₃), 1.3(t, 6H, CH₃), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 1H), 2.2 (m, 1H), 2.6(m, 1H), 2.9 (m, 1H), 2.1 (q, 2H), 3.2 (m, 2H), 3.7 (m, 1H), 4.0 (s, 3H,OCH₃), 6.1 (s, 1H_(ar)), 6.7 (s, 1H_(ar)), 8.0 (s, 1H, NH) 8.6 (5, 1H).¹³C NMR (100 MHz, CDCl₃): δ 7.36, 22.45, 23.02, 28.48, 41.35, 44.15,49.95, 53.74, 55.80, 93.65, 111.83, 136.69, 150.03, 162.87, 164.33.Expected Mol. Wt. [C₂₀H₃₃N₃O₄S] 411.2, Observed Mol. Wt. 412.2 [M+H⁺].

H): Synthesis of(4-benylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide(Compound 110)

(Ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide (500mg) was stirred in 7 mL DMF with 1.25 mL benzaldehyde and 1 mL TFA.Sodium triacetoxyborohydride (3.5 g) was added in two portions, and themixture was left to stir overnight at 40° C. The reaction mixture waspoured into aqueous NaOH and the product extracted into dichloromethaneand purified by column chromatography to afford 366 mg of compound 110.

¹H NMR (400 MHz, CDCl₃): δ 1.2 (t, 3H, CH₃), 1.2-1.3 (3, 3H,), 1.5-1.8(m, 3H), 1.8-2.0 (m, 1H), 2.3 (m, 2H), 2.6 (br s, 1H), 2.9 (m, 1H),3.1-3.3 (m, 1H), 3.7 (m, 1H), 3.8 (s, 3H), 4.5 (br s, 2H), 3.7 (m, 1H),4.0 (s, 3H, OCH₃), 6.1 (s, 1H_(ar)), 7.4 (m, 5H), 8.0 (s, 1H, NH) 8.6(5, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 7.36, 14.20, 22.91, 28.5, 41.32,47.52, 50.03, 53.65, 55.77, 62.32, 94.62, 111.36, 112.24, 126.95,128.97, 136.59, 137.43, 150.53, 162.69, 1664.15. Expected Mol. Wt.[C₂₄H₃₃N₃O₄S] 459.2, Observed Mol. Wt. 460.2 [M+H⁺].

Example 4: Membrane Permeability of Compound 102

Membrane permeability of4-methylamino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl))-2-methoxybenzamide)(Compound 102) was measured using a PAMPA assay at pH 5 and 7.4.Specifically, 10 mM solutions of controls ranitidine (3.5 mg in 1 mLDMSO) and propanolol (2.9 mg in 1 mL DMSO), N-methyl amisulpride (3.3 mgin 0.8 mL DMSO), and amisulpride (3.4 mg in 0.9 mL DMSO) were prepared.Diffusion across a Pion PAMPA membrane were measured at pH 5 and pH 7.4,as shown in Table 1, respectively

TABLE 1 Permeability of Compound 102, amisulpride, propanolol, andranitidine through a PAMPA membrane at pH 5 and 7.4. Test CompoundPermeability (cm/s) pH 5 Permeability (cm/s) pH 7.4 Amisulpride 2.4 ×10⁻¹⁰ 2.4 × 10⁻¹¹ N-methyl 2.1 × 10⁻⁸  5.2 × 10⁻⁹  amisulpride (Compound102) Promanolol 3.1 × 10⁻⁸  7.8 × 10⁻⁶  Ranitidine 1.1 × 10⁻¹⁰ 1.5 ×10⁻¹⁰

Example 5: Binding of Compound 102 to Dopamine D₂ Receptors (Cell-BasedAssay)

The ability of Compound 102 to bind dopamine D₂ receptors was measuredin a cell-based assay. Dopamine D₂ receptor cells were seeded in a halfa black, clear-bottomed 96 well plate. At a density of 15,000 cells/wellto a volume of 25 μL and were left to incubate overnight. Calcium 5 dyein HEPES buffered HBSS (Hanks' balanced salt solution) was prepared and10 μL was added to each well and the mixture was left to sit at 37° C.for 1 hour. After equilibration, 5 μL of the test compound and controlswere added to the wells and incubated at room temperature for 10minutes. Fluorescence was measured every 1.52 seconds. After 20 seconds10 μL of dopamine (at EC₈₀ concentration) was added and the fluorescencemonitored for 2 minutes with excitation at 452 nm and emission at 525nm. Cell-based IC₅₀ values for Compound 102, together with knowndopamine D₂ inhibitors risperidone, amisulpride, and clozapine arepresented in Table 2.

TABLE 2 IC₅₀ values for Compound 102, risperidone, amisulpride, andclozapine against dopamine D2 receptors (cell-based assay). Compound D₂IC₅₀ nM Compound 102 8.9 Risperidone 3.6 Amisulpride 1.5 Clozapine 7100

Example 6: Binding of Compound 102 to Dopamine D₂ Receptors (MembranePreparation)

The ability of Compound 102 to bind the dopamine D₂ receptor in amembrane preparation was examined. Medium was removed from dopamine D₂receptor cells and washed with PBS. A lysis buffer (250 mM sucrose, 1 nMEDTA, 10 mM Tris HCl buffered at pH 7.2 plus protease inhibitors) wasadded and cells scrapped using a plate scrapper. Cells were homogenizedwith 20 manual up and down strokes in a glass homogenizer. Intact cells,nuclei, and cell debris were removed by centrifugation of the homogenateat 500×g for 10 minutes at 4° C., the supernatant was removed, and thepellet resuspended in assay buffer.

Membrane preparations were incubated with ³H spiperone untilequilibration. Separation of bound from free radioligand was carried outusing a Packard Filtermate Harvester and glass filter plates.Radioactivity was measured using a Packard Topcount. To 20 μL of D₂membranes were mixed 20 μL of ³H spiperone and 10 μL test compound orreference ligand in binding buffer in a nonbinding 96 well plate, andincubated for <120 minutes. Prior to filtration, a 96 well harvestfilter plate was coated with 0.33% polyethyleneimine for 30 minutes andthen washed with assay buffer. The binding reaction was transferred tothe filter plate and washed three times with wash buffer, dried,scintillant added, and radioactivity counted on a Topcount NXT.

Compound 102, risperidone, amisulpride, and clozapine were tested using0.1 nM ³H spiperone at concentrations of 1000, 100, 10, 1, 0.1, and 0.01nM in triplicate. IC₅₀ values for this membrane based assay arepresented in Table 3.

TABLE 3 IC₅₀ values for Compound 102, risperidone, amisulpride, andclozapine against dopamine D2 receptors (membrane based assay). CompoundD₂ IC₅₀ nM Compound 102 8.2 Risperidone 10.4 Amisulpride 8.5 Clozapine2800

Example 7: Binding of Compound 102 and Compound 103 to Various CNSReceptors (Dopamine D2, Dopamine D3, a 2 Adrenergic, and 5-HT_(2a)Receptors) (Table 41

The ability of Compound 102 and 103 to bind α₂ (non-selective), α_(2A),α_(2B), α_(2C), 5-HT_(2A) (agonist), 5-HT_(2A) (antagonist), D_(2L),D_(2S), and D₃ was measured at concentrations ranging from 10×10⁻⁵ to10×10⁻⁹ M and measuring displacement of reference ligands (prazosin forα₂ (non-selective), yohimbine for α_(2A), α_(2B) and α_(2C), DOI([2,5-dimethoxy-4-iodophenyl]-2-aminopropane) for 5-HT_(2A) (agonist),ketanserine for 5-HT_(2A) (antagonist), butaclamol for D_(2L), 7-OH-DPATfor D_(2S), and (+) blutaclamol for D₃). bound to the respectiveisolated receptor. Inhibition data are reported in Table 4.

TABLE 4 IC₅₀ and Ki values for Compounds 102 (LB102) and Compound 103(LB103) against various CNS receptors in a cell based assay. IC50 (nM)Ki (nM) LB102 LB103 LB102 LB103 α-_(2A) (non-selective) 95 150 41 6.7α-_(2A)(h) 480 220 α-_(2B)(h) 170 110 α-_(2C)(h) 790 240 5-HT_(2a)(agonist) 270 550 200 410 5-HT_(2a) (antagonist) 890 980 490 530 5-HT₇74 27 D2L 2.7 1.7 0.66 0.41 D2S 8.4 1.4 3.4 0.56 D3 11 5.5 2.5 1.2

Example 8: Novel Object Recognition (NOR) Assay Showed Efficacies ofCompounds 102 and 103

Efficacy of Compounds 102 and 103 was evaluated in rats in a NovelObject Recognition (NOR) assay, a well-established model recapitulatingcognitive and negative aspects of the PANSS scale of schizophrenia. Inthis assay, animals were treated for several weeks with a low dose ofphencyclidine (PCP) to impair the ability of the rat to discern betweennovel and familiar objects. Typically rats, like humans, would spendmore time exploring a novel object than a familiar one. The efficacy inthis study was demonstrated by the ability of the test treatment torestore normal brain function as manifested by reversing the PCPimpairment.

In this NOR study the efficacy of Compounds 102 and 103 was compared toknown antipsychotics amisulpride and risperidone for its ability torestore normal differentiation between novel and familiar objectexploration in PCP-treated rats. Rats (n=10/group) were dosed with 2mg/kg intraperitoneal twice a day (i.p., b.i.d.) for seven days followedby 7 days drug free. Cognitive measurements, at various PO doses testagent, were taken at 3 hours post-dose for Compound 102, 103, andamisulpride and at 30 minutes for risperidone. Novel object explorationtime was measured for the test subjects from a sub-chronic PCP NOR studyin rats (n=10/group). The differences in exploration time between novel(Tnovel¬, ) and familiar (Tfam liar) objects are depicted in FIG. 1A (*:p<0.05; and **: p<0.01). FIG. 1B shows discrimination index of the NORstudy obtained by the following Equation 1:

Discrimination index=(time spent exploring novel−time spent exploringfamiliar)/total exploration time)  (Equation 1)

FIGS. 1A and 1B show that all doses of Compounds 102 and 103, save one,increased the difference between novel and familiar object explorationtime in a manner consistent with currently used antipsychoticsamisulpride and risperidone.

In the NOR study depicted in FIGS. 1A and 1B, Compounds 102 and 103 wereable to restore known object exploration behavior in rats treated withPCP to levels similar to untreated rats, and on par with values obtainedusing known antipsychotics Amisulpride and Risperidone.

Example 9: Amphetamine-Induced Locomotor Activity (LMA) Assay ShowedEfficacies of Compounds 102 and 103

Efficacy of Compounds 102 and 103 was studied in rats in anamphetamine-induced Locomotor Activity (LMA) assay, a measure ofpositive aspects of the PANSS scale. In the LMA assay rats were dosedwith amphetamine (Amp, 1 mg/kg, s.c.), causing excessive movement, in acage with sensors that monitored how far each rat moved. Rats dosed withamphetamine alone tended to show hypermobility while rats dosed withantipsychotics showed more normal, calmer, activity.

In this LMA study Compounds 102 (Cpd 102, 30 mg/kg) and 103 (Cpd 103, 30mg/kg), amisulpride (30 mg/kg), and risperidone (1 mg/kg) were dosedorally in groups of 10 rats. Distance moved, over the course of an hour,was measured 6 hours post dosing for Compounds 102 and 103 andamisulpride-risperidone was dosed 1 hour prior to measurement. Theendpoint of this study was total ambulatory distance (the distancetraveled by each animal in the cage). Total ambulatory distance datafrom this amphetamine induced LMA study are summarized in FIG. 2(*:p<0.01; **: p<0.05).

In this LMA study in rats, as shown in FIG. 2, the normalizedamphetamine hyperactivity of Compound 102 was statistically superior tothat of amisulpride (p<0.05), and the normalized amphetaminehyperactivity of Compound 103 was statistically indistinguishable fromthat of amisulpride (p<0.01).

REFERENCES

The references listed below, and all references cited in thespecification are hereby incorporated by reference in their entireties,as if fully set forth herein.

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1. A compound having a structure of Formula I:

including pharmaceutically acceptable salts and stereoisomers thereof, wherein: R₁ is

 and X and Z are the same or different and independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl, optionally the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroarylalkyl, and heteroaryl groups are further substituted with one or more substitution groups selected from the group consisting of halogens such as chlorine, bromine and fluorine, amines, hydroxy groups, carboxylic acids, nitro groups, carbonyl and other alkyl and aryl groups as defined herein; with the proviso that at least one of X and Z is not hydrogen.
 2. The compound of claim 1, wherein the compound is a stereoisomer having a structure of Formula I-S:

including pharmaceutically acceptable salts thereof.
 3. The compound of claim 1, wherein R₁ is


4. The compound of claim 1, wherein R₁ is


5. The compound of claim 1 4, wherein X and Z are the same or different and independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, and heteroaryl, optionally the alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups are further substituted with one or more substitution groups selected from the group consisting of halogens such as chlorine, bromine and fluorine, amines, hydroxy groups, carboxylic acids, nitro groups, carbonyl and other alkyl and aryl groups as defined herein; with the proviso that at least one of X and Z is not hydrogen.
 6. The compound of claim 1, wherein X is H.
 7. The compound of claim 6, wherein X═H and Z═CH₃.
 8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 9. A method of delivering into the brain of a subject a dopamine and/or serotonin and/or α2 receptor antagonist comprising administering to the subject a therapeutically effective amount of the compound of claim 1, wherein the level of the dopamine and/or serotonin and/or α2 receptor antagonist in brain is higher than the level of amisulpride when amisulpride is administered to the subject at a comparable dose.
 10. A method of antagonizing dopamine and/or serotonin and/or α₂ receptor in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 1, either individually or in combination with other CNS active agents.
 11. A method of treating one or more conditions responsive to modulation of dopamine and/or serotonin and/or α₂ receptor in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 1, either individually or in combination with other CNS active agents.
 12. A method of treating one or more disorders associated with an abnormality in levels of dopamine and/or serotonin in the brain of a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim
 1. 13. The method of claim 11, wherein the disorder or condition is a mental illness.
 14. The method of claim 13, wherein the mental illness is schizophrenia.
 15. The method of claim 10, wherein the method further comprising administering to the subject a therapeutically effective amount of another medication.
 16. The method of claim 10, wherein the disorder or condition is selected from the group consisting of depression, bipolar disorder, Tourette's syndrome, Schizoaffective disorder, Parkinson's psychosis, Alzheimer's psychosis, oppositional defiant disorder, childhood schizophrenia, dysthymia, treatment resistant schizophrenia, chronic fatigue syndrome, and predominantly negative symptoms of schizophrenia. 17-26. (canceled)
 27. The method of claim 10, wherein the serotonin receptor is 5-HT_(2a) receptor.
 28. The method of claim 10, wherein the α2 receptor is selected from the group consisting of α2A receptor, α2B receptor, α2C receptor, and combinations thereof. 29-30. (canceled) 